The purpose of this grant application is to complete a placebo-controlled, randomized, Phase 2 clinical trial to test the hypothesis that dietary supplementation with a high dose of the long-chain omega-3 polyunsaturated fatty acid DHA is beneficial in retarding the progressive retinal degeneration and associated loss of visual function in patients with XLRP. XLRP is one of the most severe forms of hereditary retinal degeneration with an onset in early childhood and is characterized by night-blindness, decreased acuity, and tunnel vision/legal blindness due to a very slow degeneration of rod and cone photoreceptors. There is no cure for XLRP and treatment of symptoms is limited. Although the disease has distinct genetic origins, nutrition may ultimately influence the rate of progression. The high level (greater than 30%) of DHA in photoreceptors is suggestive of a role in maintaining the integrity of retinal membranes surrounding the enzymes responsible for phototransduction. From previous results, a high dose of dietary DHA based on bodyweight should sufficiently elevate blood DHA in patients with early stage XLRP (ages 7 to 32 years) to a level estimated to slow the loss of cone photoreceptor function. Capsule intake is 30 milligrams DHA/kilogram/day so as to target a red blood cell (RBC)-DHA level of roughly 12 to13% of total fatty acids. Annual vision tests are: full-field cone electroretinographic (ERG) responses to 31-Hertz flicker as the primary functional outcome, rod ERGs, a-wave rod and cone ERG photoreceptor assessment, visual acuity, visual fields, fundus photography, dark-adapted thresholds, ocular coherence tomography (OCT) and comprehensive eye exams. Blood DHA analysis (every 6 months) and biosafety measures (annually) assess RBC fatty acids, platelet aggregation, plasma vitamins A and E, plasma antioxidant capacity, plasma malonyldialdehyde, plasma oxidized low-density lipoprotein (LDL), lipoprotein lipids, and comprehensive metabolic blood chemistry. The rarity of this disease resulted in a prolongation of the recruitment period. The first of the 55 active participants enrolled beginning on August 1, 2005, and last enrolled June 6, 2008. Thus, completion of the 4-year intervention supplement ended August 1, 2009 for the first enrollee and will end June 15, 2012 for the last. This application proposes to extend supplementation and annual testing of the participants beyond 4 years as we will not be able to disclose group assignments until June 2012. The additional data collected will be used in ancillary data analysis to evaluate longer term efficacy of the DHA intervention. As of January 31, 2010, 3 participants are in their second year of supplementation, 18 in their third year, 21 in their fourth year and 13 have begun their fifth year on the trial. With a sample size of 55 active participants, 24 subjects per group (placebo and DHA-supplemented) have remained to attain statistical significance in this 4-year trial. Based on Phase 1 clinical trial results, a high dose of dietary DHA shows promise in retarding progression of this blinding eye disease.